An overview of Clinical Quality Registries (CQRs) on gynecological oncology worldwide.

INTRODUCTION: Clinical Quality Registries (CQRs) were initiated in order to compare clinical outcomes between hospitals or regions within a country. To get an overview of these CQRs worldwide the aim of this study was to identify these CQRs for gynecological oncology and to summarize their characteristics, processes and QI's and to establish whether it is feasible to make an international comparison in the future. METHODS: To identify CQRs in gynecological oncology a literature search in Pubmed was performed. All papers describing the use of a CQR were included. Administrative, epidemiological and cancer registries were excluded as these registries do not primarily serve to measure quality of care through QI's. The taskforce or contact person of the included CQR were asked to participate and share information on registered items, processes and indicators. RESULTS: Five nations agreed to collaborate: Australia, Denmark, Italy, the Netherlands and Sweden. Denmark, Netherlands and Sweden established a nationwide registry, collecting data on multiple tumor types, and various QI's. Australia and Italy included patients with ovarian cancer only. All nations had a different process to report feedback results to participating hospitals. CONCLUSION: CQRs serve the same purpose to improve quality of care but vary on different aspects. Although similarities are observed in the topics measured by the QI's, an international comparison was not feasible as numerators or denominators differ between registries. In order to compare on an international level it would be useful to harmonize these registries and to set an international standard to measure the quality of care with similar indicators.

Prognostic value of the 2018 FIGO staging system for cervical cancer.

OBJECTIVE: To compare the prognostic performance of the FIGO 2009 and FIGO 2018 staging systems for cervical cancer (CC) in regards to risk stratification, survival and treatment outcome. METHODS: A total of 4461 CC patients diagnosed in Denmark during 2005-2018 were identified through the Danish Gynaecological Cancer Database and restaged from the 2009 FIGO to the 2018 FIGO staging system. 5-year survival estimates were made for each group. Also, association between lymphovascular space invasion (LVSI) and lymph node metastasis (LNM) was assesed for tumors with a horizontal spread >7 mm and depth of invasion ≤5 mm. RESULTS: Overall, stage migration was observed in 41.4% of our cases due to the introduction of stage IIIC (20.1%), refined tumor size criteria within stage I (76.2%), and use of radiological findings to define stage IV (3.7%). 5-year overall survival increased for all stages except IA2, IIA2, IIIA and IIIB. Restaging of 2009 IB1 to 2018 FIGO resulted in significant stage allocations. Furthermore, an association between LVSI and LNM was observed in squamous cell carcinomas with a depth of invasion of 3-5 mm and a horizontal spread >7 mm (p = 0.03). CONCLUSION: The 2018 FIGO staging system provided improved discriminatory ability for stage I and IV. Grouping all patients with positive pelvic or paraortal lymph nodes to stage IIIC led to pronounced heterogenous survival rates within these stages. Lymph node assessment was proven imperative in FIGO 2018 IA2 squamous cell carcinomas with a depth of invasion of 3-5 mm, a horizontal spread >7 mm and LVSI.

The value of surgical staging in patients with apparent early stage epithelial ovarian carcinoma.

OBJECTIVE: The value of surgical staging of apparent early stage epithelial ovarian carcinoma (EOC) is unclear. The aim of this study was to evaluate the importance of surgical staging on the stage of disease and treatment plan. MATERIAL AND METHODS: All patients with apparent stage I EOC undergoing staging from 01/01/2005 to 30/06/2017 in all Danish hospitals and in the Radboud University Hospital Nijmegen, the Netherlands, were evaluated to identify the pathological findings responsible for upstaging and changes in treatment plans. RESULTS: We included 1234 patients with apparent stage I EOC. The staging steps often missed were the biopsy from the right diaphragmatic surface (missed in 96.9% of all patients) and lymph node (LN) sampling or lymphadenectomy (missed in 65.5% of all patients). Upstaging occurred in 393 patients (31.8%) due to microscopic spread to both ovaries (0.8%); ovarian surface (5.8%); positive cytology (10.0%); fallopian tubes (3.1%), ovary (1.5%) and/or uterus serosa (1.2%); pelvic peritoneum (4.3%); LNs (4.7%); omentum (3.7%); abdominal peritoneum (0.6%) and right diaphragmatic surface (2.6%). Of the 393 upstaged patients, 138 (35.1%) had an altered treatment plan due to metastases found by surgical staging. CONCLUSION: Staging was incomplete in most patients, mainly because a biopsy of the diaphragm was omitted. However, surgical staging led to adjuvant treatment in 35.1% of the upstaged patients. Peritoneal biopsies (para-colic gutters and right diaphragm) were of little value, since few patients had an adjustment of treatment plan due to these biopsies. Omitting these biopsies, in the absence of peritoneal abnormalities, is justifiable.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Vaginal Radical Trachelectomy for early stage cervical cancer. Results of the Danish National Single Center Strategy.

OBJECTIVE: To present and evaluate an unselected national single center strategy with fertility preserving trachelectomy in cervical cancer. In 2003 nationwide single-center referral of women for trachelectomies was agreed upon between all Danish departments performing cervical cancer surgery with the purpose of increasing volume, to increase surgical safety and facilitate follow-up. METHODS: Prospective data were recorded in the Danish Gynecological Cancer Database of all Vaginal Radical Trachelectomies (VRT) performed in Denmark between 2002 and 2013. Oncologic, fertility and obstetrical outcomes of 120 unselected consecutive VRTs were assessed. To obtain complete follow-up about fertility treatment, pregnancy and obstetric outcome the women filled out an electronic questionnaire. Median follow-up: 55.7 months. RESULTS: 85.8% of the patients had stage IB1 disease, 68.3% squamous cell carcinomas, 30.0% adenocarcinomas and 1.7% adenosquamous carcinomas. Six recurrences (5.1%) and 2 deaths (1.7%) occurred. Four women with adenocarcinomas (10.5%) had recurrences, compared to two women with squamous cell carcinomas (2.5%). Seventy-two women (60.0%) desired to conceive and 55 women obtained a total of 77 pregnancies. Of the 72 women 40 were referred to fertility treatment. First and second trimester miscarriage rates were 21.6% and 2.7%, respectively. A total of 53 children were born of which 41 were delivered after gestational week 34. CONCLUSION: This unselected national single center referral study confirms the oncological safety of Vaginal Radical Trachelectomy. The complete follow-up regarding reproductive data, reveals a surprisingly extensive need of fertility treatment and due to the rate of prematurity, these pregnancies must be regarded as high-risk pregnancies.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Oral contraceptive use and impact of cumulative intake of estrogen and progestin on risk of ovarian cancer.

PURPOSE: Oral contraceptive use decreases the risk of ovarian cancer, but no previous studies have assessed the impact of cumulative intake of estrogen and progestin on ovarian cancer risk. METHODS: We used data from a population-based case­control study conducted in Denmark in 1995­1999 among women aged 35­79 years; 554 women with epithelial ovarian cancer and 1,564 age-matched controls were included in the analyses. Data were analyzed in multiple logistic regression models. RESULTS: The use of combined oral contraceptives only and the mixed use of combined and progestin-only pills decreased the risk of ovarian cancer, while no association was found with exclusive use of progestin-only pills. No major differences in risk were found for users of combined oral contraceptives with high- and low-potency estrogen and progestin. There was no effect of cumulative progestin intake, but decreased risks of ovarian cancer with increasing cumulative intake of estrogen (OR = 0.82; 95 % CI 0.67­0.99, per 100 mg estrogen) and increasing duration of oral contraceptive use (OR = 0.95; 95 % CI 0.92­0.98, per year of use) were found. No effect of cumulative estrogen intake was found, however, after adjustment for duration of oral contraceptive use. CONCLUSIONS: The protective effect of oral contraceptives against ovarian cancer may be sufficiently explained by duration of anovulation. This suggests that if the estrogen and progestin doses are sufficient to cause anovulation, a higher intake of estrogen or progestin confers no extra protection against ovarian cancer.

Socioeconomic position and survival after cervical cancer: influence of cancer stage, comorbidity and smoking among Danish women diagnosed between 2005 and 2010.

BACKGROUND: In an attempt to decrease social disparities in cancer survival, it is important to consider the mechanisms by which socioeconomic position influences cancer prognosis. We aimed to investigate whether any associations between socioeconomic factors and survival after cervical cancer could be explained by socioeconomic differences in cancer stage, comorbidity, lifestyle factors or treatment. METHODS: We identified 1961 cases of cervical cancer diagnosed between 2005 and 2010 in the Danish Gynaecological Cancer database, with information on prognostic factors, treatment and lifestyle. Age, vital status, comorbidity and socioeconomic data were obtained from nationwide administrative registers. Associations between socioeconomic indicators (education, income and cohabitation status) and mortality by all causes were analysed in Cox regression models with inclusion of possible mediators. Median follow-up time was 3.0 years (0.01-7.0). RESULTS: All cause mortality was higher in women with shorter rather than longer education (hazard ratio (HR), 1.46; 1.20-1.77), among those with lower rather than higher income (HR, 1.32; 1.07-1.63) and among women aged<60 years without a partner rather than those who cohabited (HR, 1.60; 1.29-1.98). Socioeconomic differences in survival were partly explained by cancer stage and less by comorbidity or smoking (stage- and comorbidity-adjusted HRs being 1.07; 0.96-1.19 for education and 1.15; 0.86-1.52 for income). CONCLUSION: Socioeconomic disparities in survival after cervical cancer were partly explained by socioeconomic differences in cancer stage. The results point to the importance of further investigations into reducing diagnosis delay among disadvantaged groups.

Does the use of diagnostic PET/CT cause stage migration in patients with primary advanced ovarian cancer?

OBJECTIVE: To investigate if the use of diagnostic FDG-PET/CT leads to stage migration in patients with advanced ovarian cancer and to evaluate the prognostic significance of FDG-PET/CT. METHODS: From September 2004 to August 2007, 201 patients with a Risk of Malignancy Index (RMI) >150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. On 15 August, 2009 overall survival and prognostic variables were analysed in 66 ovarian cancer patients (64 stage III and 2 stage IV). RESULTS: Median follow-up was 30.2 months; median age was 62.5 years (range 35-85 years); 97% (64/66) had a performance status

Preoperative serum tetranectin, CA125 and menopausal status used as single markers in screening and in a risk assessment index (RAI) in discriminating between benign and malignant ovarian tumors.

OBJECTIVES: To improve the poor survival in ovarian cancer (OC) patients, the research has been focused on new OC markers. One aim is to find markers to identify the cancers in early preclinical stages by screening. Another aim is to find new diagnostic markers, which may select patients at high risk for OC for quick referral to highly specialized centers in gynecologic oncology. These aims were addressed in the present study by evaluating serum tetranectin (TN) and serum CA125 on a large number of pre- and postmenopausal women with ovarian tumors and controls. METHODS: The potential ability of the markers to discriminate between the four groups (208 benign ovarian tumor, 153 borderline ovarian tumor (BOT), 445 OC and 1333 age matched controls) in OC screening was examined. We also constructed a risk assessment index (RAI) for discrimination between tumor groups based on these variables and menopausal status. RESULTS: Highly significant differences in both TN and CA125 levels were found between all the four groups as well as between the different FIGO stages of OC patients. A very high probability of having OC or a benign tumor, respectively, was predicted by the RAI. CONCLUSIONS: In the case-control part of the study, we found that TN and CA125 deserve to be validated on pre-clinical samples by inclusion in future marker panels. The RAI is also a potential new candidate for a diagnostic tool for selecting patients at high risk for having OC; hence it deserves further evaluation in a prospective clinical study.

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Prediction of suboptimal primary cytoreduction in primary ovarian cancer with combined positron emission tomography/computed tomography--a prospective study.

OBJECTIVE: To prospectively identify combined PET/CT predictors of incomplete/suboptimal primary cytoreduction in advanced ovarian cancer. METHODS: From September 2004 to March 2007, 179 patients with a Risk of Malignancy Index (RMI) >150 based on serum CA-125, ultrasound examinations and menopausal state, underwent PET/CT within 2 weeks prior to standard surgery/debulking of a pelvic tumor. Ten PET/CT features were identified and evaluated as predictors of cytoreduction in 54 patients with advanced ovarian cancer. RESULTS: Complete cytoreduction (no macroscopic residual disease) was achieved in 35% and optimal cytoreduction (<1 cm residual disease) was achieved in 56%. Using univariate analysis, predictors of incomplete cytoreduction were large bowel mesentery implants (LBMI) (P<0.003), pleural effusion (P<0.009), ascites (P<0.009) and peritoneal carcinosis (P<0.01). LBMI (P<0.03) and ascites (P<0.05) were also predictors of suboptimal cytoreduction. Using multivariate analysis, LBMI was the only independent predictor of incomplete cytoreduction (P=0.004) and no predictor of suboptimal cytoreduction was found. CONCLUSION: PET/CT predictors of cytoreduction were found. But they should not be used to withhold patients form primary cytoreductive surgery. We suggest PET/CT as a supplementary image modality prior to surgery in primary OC patients whenever accurate and comprehensive preoperative evaluation of primary tumor and metastases is desired.

The relation of germ cells per tubule in testes, serum inhibin B and FSH in cryptorchid boys.

At bilateral orchiopexy bilateral biopsies may be indicated to determine fertility potential. It is currently unknown if the serum inhibin B levels at time of orchiopexy reflect the testicular status of the bilaterally cryptorchid child. The aim of this study was to relate the results of inhibin B and FSH measurements with testicular biopsy parameters in bilateral cryptorchid boys. Included were 25 boys with bilateral cryptorchidism, median 2.5 years (9 months to 5.5 years) at surgery for bilateral cryptorchidism with simultaneous testicular biopsies, and blood sample for inhibin B and FSH. The number of spermatogonia and gonocytes was measured in 100 tubular transverse sections, the S/T and the mean-S/T of the patient was found, and expressed as percent of lowest normal value. Inhibin B and FSH were measured and related to age-specific values. Forty percent (10/25) of the patients had very low mean-S/T (mean-S/T<10% of lowest normal-value). Inhibin B was decreased in 24% (6/25) of the patients, all with decreased mean-S/T, predominantly with a mean-S/T<10% of lowest normal-value (p<0.05). There was a negative correlation between inhibin B and FSH (p<0.05). In cases of mean-S/T<10% of lowest normal-value and decreased inhibin B, we found increased FSH in 9% (2/22) of the patients and hypergonadotropic hypogonadism was suspected. Low FSH was found in 5% (1/22) of the patients and hypogonadotropic hypogonadism was suspected. Low inhibin B predicts a serious condition in respect of infertility. Low FSH and inhibin B indicates examination for hypogonadotropic hypogonadism. In bilateral cryptorchid boys inhibin B levels correlated negatively to FSH.

Do risk factors for epithelial ovarian cancer have an impact on prognosis? Focus on previous pelvic surgery and reproductive variables.

OBJECTIVES: The prognostic impact of risk factors for ovarian cancer development is sparsely explored, but previous sterilisation has been shown to have a negative impact on survival. METHODS: Ovarian cancer cases were from the Danish MALOVA study. Information on previous pelvic surgery as well as reproductive variables was obtained from a personal interview conducted closely after primary surgery. Cox regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for ovarian cancer specific death in relation to previous pelvic surgery and reproductive variables including lifetime number of ovulation years. RESULTS: A total of 295 women with Stage III ovarian carcinomas were identified and followed to death or for a median of 7.3 years (range 5.4-9.5 years). Previously sterilised or hysterectomised women seemed to have a slightly decreased risk of ovarian cancer death (HR = 0.62; 95% CI: 0.36-1.08 and HR = 0.82; 95% CI: 0.55-1.21), although none of these associations reached statistical significance. The prognostic impacts of the individual reproductive variables followed the same pattern as the impact of the variables on ovarian cancer development, although significance was only reached for age at menarche (HR = 0.91 per year; 95% CI: 0.84-0.99). By accumulation of the possible minor effects of the reproductive variables in calculation of the total lifetime number of ovulation years, we found that survival decreased significantly with increasing number of ovulations (HR = 1.53 per 10 years; 95% CI: 1.09-2.14). CONCLUSION: Increasing lifetime number of ovulations was a negative prognostic factor for ovarian cancer specific survival. Previous sterilisation or hysterectomy seemed to be associated with improved survival.

Tetranectin in cerebrospinal fluid of patients with multiple sclerosis.

OBJECTIVE: Tetranectin (TN) is a glycoprotein and C-type lectin thought to play a prominent role in tissue remodelling. The aim of this study was to determine the TN serum and cerebrospinal fluid (CSF) concentration in patients with multiple sclerosis (MS) and controls. MATERIAL AND METHODS: Two-hundred-and-four patients, divided into four diagnostic groups, i.e. definite MS (n = 76), possible onset symptoms of MS (n = 48), other non-inflammatory neurological diseases (n = 61) and other inflammatory neurological diseases (n = 19) and 47 controls with no history of neurological disease were analysed for TN in serum and CSF using a polyclonal sandwich ELISA. RESULTS: All tested groups, e.g. definite MS, possible onset symptoms of MS, other neurological disease, both inflammatory and non-inflammatory, had decreased concentrations of TN in the CSF compared to the concentrations in controls. The quotient of TN in CSF divided by the concentration in serum (QTN) correlated significantly with the same quotient of albumin (QALB), was significantly correlated with the same quotient of albumin QALB. To account for differences in blood brain barrier permeability, we calculated a TN-index defined as: TN-index = QTN/QALB. QTN was significantly decreased in all groups compared to that in controls. However, in definite MS and patients with first attack of MS, the TN-index was not significantly different from that of controls. In contrast, other neurological diseases, both inflammatory and non-inflammatory, were associated with a decreased TN-index. CONCLUSION: These results indicate that TN may play a role in neurological diseases and may serve as a diagnostic aid in MS.

Pre-treatment prediction of chemoresistance in second-line chemotherapy of ovarian carcinoma: value of serological tumor marker determination (tetranectin, YKL-40, CASA, CA 125).

OBJECTIVE: To examine if the determination of the levels of serological tumor markers at time of relapse had any predictive value for chemoresistance in the second-line treatment of ovarian cancer patients. METHODS: From a registry of consecutive single-institution patients with epithelial ovarian carcinoma pretreated with paclitaxel plus platinum, we selected 82 patients with (a) solid tumor recurrence, and (b) second-line chemotherapy consisting of topotecan (platinum-resistant disease) or paclitaxel plus carboplatin (platinum-sensitive disease). Stored serum samples were analyzed for the biochemical tumor markers tetranectin, YKL-40, CASA (cancer-associated serum antigen), and CA 125. The serum tumor marker levels at time of relapse were correlated with response status at landmark time after 4 cycles of second-line chemotherapy. Univariate and multivariate logistic regression analyses (chemoresistant vs non-chemoresistant disease) were performed. RESULTS: At landmark time, 26% of patients had progression according to the GCIG (Gynecologic Cancer Intergroup) progression criteria. In univariate logistic regression analysis, the tumor markers tetranectin (OR 0.4; 95% CI: 0.2-0.8; p=0.008), YKL-40 (OR 1.8; 95% CI: 1.0-3.3; p=0.045), and CASA (OR 1.8; 95% CI: 1.2-2.7; p=0.007) had predictive value for second-line chemoresistance, whereas serum CA 125 had no predictive value. In a multivariate logistic regression analysis, serum tetranectin and CASA both had independent predictive value for chemoresistance. The combined determination of tetranectin and CASA had a specificity of 90% with 33% sensitivity for the prediction of chemoresistance (area under the receiver operating characteristic curve = 0.78; 95% CI: 0.66-0.91; p=0.001). CONCLUSION: Low serum levels of tetranectin, or high serum levels of CASA or YKL-40, are associated with increased risk of second-line chemoresistance in patients with ovarian cancer.

Increased risk of ovarian cancer in integrin beta3 Leu33Pro homozygotes.

We previously demonstrated that integrin beta(3) Leu33Pro homozygotes have an increased risk of cancer, possibly most pronounced for ovarian cancer. We now test the latter hypothesis in case-control and prospective studies. We genotyped 463 Danish women with ovarian cancer, and 4291 women from the Danish general population. Calculation of odds ratios by conditional logistic regression was performed in the case-control study (n = 463 + 3543), and of ovarian cancer incidence, log-rank statistics and hazard ratios by Cox regression in the prospective study (n = 4291) with 9.5-year follow-up. In the case-control study matched for age and marital status, the odds ratio for ovarian cancer in homozygotes versus non-carriers was 1.6 (95% confidence interval: 1.0-2.6). In the prospective study with 28 incident ovarian cancers, non-carriers and homozygotes had incidences of 7 (4-11) and 30 (10-92) per 10 000 person-years (log-rank P = 0.02). The age-adjusted hazard ratio for ovarian cancer in homozygotes versus non-carriers was 3.9 (1.1-13). Risk of ovarian cancer did not differ between heterozygotes and non-carriers in either study. Integrin beta(3) Leu33Pro homozygotes have an increased risk of ovarian cancer.

Cancer-associated serum antigen level: a novel prognostic indicator for survival in patients with recurrent ovarian carcinoma.

The aim was to examine the value of the pretherapeutic serum cancer-associated serum antigen (CASA) level as a prognostic factor for survival in patients with recurrent epithelial ovarian carcinoma. Serum levels of CASA and cancer antigen (CA)125 were prospectively determined in 70 consecutive patients with recurrent ovarian cancer before the start of second-line chemotherapy. Univariate and multivariate analyses of survival were performed. The median level of serum CASA was 6.5 U/mL (range: 0.2-1437 U/mL). Univariate analysis showed that patients with a CASA level >10.0 U/mL had significantly shorter survival than patients with CASA level < or =10.0 U/mL (P= 0.002). Using different CASA cutoff levels (6.0, 6.5, and 10.0 U/mL), multivariate Cox analyses identified CASA as an independent prognostic factor for survival at every cutoff level. The strongest prognostic function for CASA was found at a cutoff level of 10.0 U/mL (>10 vs < or =10 U/mL; hazard ratio, 2.7; 95% confidence interval, 1.6-4.7; P < 0.001). The pretreatment CA125 level was not found to be significantly associated with survival by any of the cutoffs (35, 65, 132, and 339 U/mL). A pretreatment elevated level of the tumor marker CASA is an adverse prognostic factor for survival in patients with ovarian cancer relapse.